Abstract Advances in both experimental and computational biology are helping make exciting discoveries in many fields of biology and biomedicine today. Together, physical experiments and modeling are solving fundamental puzzles in biology as well as applying the findings to medicine and technology through molecular design, targeted therapies, and nanotechnology. The PI's computational biology /biophysics lab focuses on solving fundamental structural and dynamical questions concerning nucleic acids and their complexes (notably chromatin and RNA) in collaboration with experimentalists by innovative molecular models and computational methods using ideas from mathematics, computer science, and engineering, as well as biology and chemistry. This MIRA project would consolidate three NIGMS projects on chromatin structure, RNA design, and RNA structure prediction to advance our fundamental understanding of structure/function relationships for chromatin and RNA using multiscale models that bridge disparate scales to allow unprecedented applications regarding chromatin and RNA folding. For chromatin, the detailed atomic information on nucleosomes and long-range contact maps available from genome-wide experiments will be bridged by a hierarchy of tunable coarse-grained models to link atomic, mesoscale, and polymer models to investigate the epigenetic modulation of chromatin higher-order structure by gene looping mechanisms in cancer cells; these structural mechanisms for repression/ activation of transcription have translational ramifications through targeted re-expression of those silenced genes by chromatin loop dissolution for cancer therapy. For RNA, the general problem of poor predictions of RNA and RNA/protein tertiary motifs will be tackled by exploiting the drastic variable reduction and natural modularity of 2D graphs to combine efficient coarse-grained graph sampling, graph theory substructuring, and data-mining with improved handling of pseudoknots, kink-turns, and RNA-protein-binding motifs in our program RAGTOP. We will contribute to community efforts like RNA-puzzles; design novel RNAs for predicted, but yet undiscovered, RNA-like fold motifs to produce a atlas of modules for design; and design riboswitches with desired fluorescent properties, as sensors. These works, with support from leading experts in chromatin and RNA structure and function, will help advance fundamental areas of biology /biomedicine including genome biophysics, chromatin higher-order structure, gene expression, and cell development and differentiation and hence the targeted treatment of human diseases associated with aberrant gene expression, including cancers, genetic disorders, and degenerative diseases. The resulting multiscale computing paradigms are widely applicable to other biomolecular processes and will be shared with the community at large.